scholarly journals T cell recognition of an HLA-A2-restricted epitope derived from a cleaved signal sequence.

1994 ◽  
Vol 180 (5) ◽  
pp. 1989-1994 ◽  
Author(s):  
M Guéguen ◽  
W E Biddison ◽  
E O Long
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Signal Sequence ◽  
Alternative Pathway ◽  
Cell Epitope ◽  
Cell Recognition ◽  
T Cell Epitope ◽  
T Cell Recognition ◽  
In Cells

An alternative pathway for class I-restricted antigen presentation has been suggested on the basis of peptides bound to HLA-A2 molecules in cells lacking the transporter for antigen presentation (TAP). Most of these peptides were derived from signal sequences for translocation into the endoplasmic reticulum (ER). However, it is not known whether these peptides can be presented to T cells. The hydrophobic nature of an HLA-A2-restricted T cell epitope (M1 58-66) was exploited to test whether it could be presented to T cells when derived from a signal sequence. Replacing the signal sequence of the influenza virus hemagglutinin molecule H3 with an artificial sequence containing that HLA-A2-restricted T cell epitope resulted in efficient translocation of H3 molecules into the ER and transport to the cell surface. This signal sequence-derived epitope was presented to HLA-A2-restricted T cells. Involvement of cytosolic processing for this presentation is very unlikely, because (a) presentation occurred in cells lacking TAP; (b) expression of H3 molecules with the artificial signal sequence did not produce a detectable cytosolic form of H3; and (c) presentation of the same epitope expressed in cytosolic forms of antigen required TAP. Thus, a peptide derived from a signal sequence cleaved in the ER can provide an epitope for HLA-A2-restricted T cell recognition.

scholarly journals Inhibition of T cell and antibody responses to house dust mite allergen by inhalation of the dominant T cell epitope in naive and sensitized mice.

1993 ◽  
Vol 178 (5) ◽  
pp. 1783-1788 ◽  
Author(s):  
G F Hoyne ◽  
R E O'Hehir ◽  
D C Wraith ◽  
W R Thomas ◽  
J R Lamb
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Epitope ◽  
Cell Recognition ◽  
T Cell Epitope ◽  
T Cell Recognition ◽  
Dust Mite ◽  
Der P 1

Antigen-specific CD4+ T cells play an important role in the allergic immune response to house dust mite (HDM) allergens in humans. The group 1 allergen of Dermatophagoides spp. is a major target antigen in both B and T cell recognition of HDM. In vitro studies have shown that the presentation of peptides to human T cells under appropriate conditions may lead to a state of specific nonresponsiveness. Therefore, to determine if peptides are able to modulate the function of allergen-reactive T cells in vivo, we have used a murine model of T cell recognition of the HDM allergen Der p 1. The results demonstrate that inhalation of low concentrations of peptide containing the major T cell epitope of Der p 1 (residues 111-139), induces tolerance in naive C57BL/6J mice such that they become profoundly unresponsive to an immunogenic challenge with the intact allergen. When restimulated in vitro with antigen, lymph node T cells isolated from tolerant mice secrete very low levels of interleukin 2, proliferative poorly, and are unable to provide cognate help to stimulate specific antibody production. Furthermore, intranasal peptide therapy was able to inhibit an ongoing immune response to the allergen in mice and this has potential implications in the development of allergen-based immunotherapy.

scholarly journals HIV Controllers Exhibit Effective CD8+ T Cell Recognition of HIV-1-Infected Non-activated CD4+ T Cells

Cell Reports ◽  
2019 ◽  
Vol 27 (1) ◽  
pp. 142-153.e4 ◽  
Author(s):  
Blandine Monel ◽  
Annmarie McKeon ◽  
Pedro Lamothe-Molina ◽  
Priya Jani ◽  
Julie Boucau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Hiv Controllers ◽  
Hiv 1

scholarly journals Pathogenic Potential of Borna Disease Virus Lacking the Immunodominant CD8 T-Cell Epitope

2007 ◽  
Vol 81 (20) ◽  
pp. 11187-11194 ◽  
Author(s):  
Kirsten Richter ◽  
Karen Baur ◽  
Andreas Ackermann ◽  
Urs Schneider ◽  
Jürgen Hausmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Neurological Disease ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Epitope ◽  
Wild Type ◽  
Antiviral T Cells ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is a highly neurotropic, noncytolytic virus. Experimentally infected B10.BR mice remain healthy unless specific antiviral T cells that infiltrate the infected brain are triggered by immunization. In contrast, infected MRL mice spontaneously mount an antiviral T-cell response that can result in meningoencephalitis and neurological disease. The antiviral T cells may, alternatively, eliminate the virus without inducing disease if they are present in sufficient numbers before the virus replicates to high titers. Since the immune response of H-2k mice is directed mainly against the epitope TELEISSI located in the viral nucleoprotein N, we generated BDV mutants that feature TQLEISSI in place of TELEISSI. We show that adoptive transfer of BDV N-specific CD8 T cells induced neurological disease in B10.BR mice persistently infected with wild-type BDV but not with the mutant virus expressing TQLEISSI. Surprisingly, the mutant virus replicated less well in adult MRL wild-type mice than in mutant mice lacking mature CD8 T cells. Furthermore, when MRL mice were infected with the TQLEISSI-expressing BDV mutant as newborns, neurological disease was observed, although at a lower rate and with slower kinetics than in mice infected with wild-type virus. These results confirm that TELEISSI is the major CD8 T-cell epitope in H-2k mice and suggest that unidentified minor epitopes are present in the BDV proteome which are recognized rather efficiently by antiviral T cells if the dominant epitope is absent.

Diversity of HLA Class I and Class II Restricted Minor Histocompatibility Antigens in Graft-Versus-Leukemia Reactivity.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4084-4084
Author(s):  
Marieke Griffioen ◽  
M. Willy Honders ◽  
Anita N. Stumpf ◽  
Edith D. van der Meijden ◽  
Cornelis A.M. van Bergen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hematopoietic Cells ◽  
Cd4 T Cell ◽  
Cell Recognition ◽  
T Cell Clones ◽  
T Cell Recognition ◽  
Cell Clones ◽  
T Cell Clone ◽  
Ifn Γ

Abstract Abstract 4084 Poster Board III-1019 Donor lymphocyte infusion (DLI) can be an effective cellular immunotherapy for patients with hematological malignancies after HLA-matched allogeneic stem cell transplantation (alloSCT). The effect of DLI is mediated by donor derived T-cells recognizing minor histocompatibility antigens (mHags) encoded by single nucleotide polymorphisms (SNPs) on malignant cells of the recipient. Donor T-cells may also induce Graft-versus-Host Disease (GvHD) when directed against mHags with broad expression on non-malignant tissues. The aim of this study was to investigate the specificity and diversity of mHags recognized by T-cells in Graft-versus-Leukemia (GvL) reactivity. Activated (HLA-DR+) CD8+ and CD4+ T-cell clones were isolated from a patient successfully treated with DLI for relapsed chronic myeloid leukemia (CML) more than one year after HLA-matched alloSCT. GvL reactivity in this patient was accompanied with mild GvHD of the skin. Isolated T-cell clones were shown to recognize 13 different mHags. CD8+ T-cell clones were specific for HA-1 and HA-2 in HLA-A*0201, one unknown mHag in B*0801 and 4 unknown mHags in B*4001. CD4+ T-cell clones were specific for one unknown mHag in HLA-DQ and 5 unknown mHags in DR. By screening plasmid (class I) and bacteria (class II) cDNA libraries, we identified a mHag in HLA-DQ encoded by the PI4K2B gene (Griffioen et al., PNAS 2008), 4 mHags in HLA-DR encoded by the PTK2B, MR-1, LY75 and MTHFD1 genes (Stumpf et al., Blood 2009) and a mHag in B*4001 encoded by the TRIP10 gene. For the 3 T cell clones recognizing unknown mHags in B*4001, we performed Whole Genome Assocation scanning (WGAs). A panel of 60 EBV-LCL was retrovirally-transduced with B*4001 and tested for T-cell recognition. In parallel, genomic DNA was isolated and more than one million single nucleotide polymorphisms (SNPs) were determined by the Illumina beadchip array. Statistical analysis revealed significant association between T-cell recognition of EBV-LCL and the presence of coding SNPs in the SON DNA-binding protein and SWAP-70 genes. To get more insight into the role and potential use of the mHags in GvL reactivity and GvHD, all T-cell clones were analyzed in detail for reactivity against hematopoietic and non-hematopoietic cells. Hematopoietic cells included peripheral blood cells (monocytes, B-cells and T-cells), professional antigen presenting cells (APC) and leukemic cells (CML, ALL and AML). All CD8+ T-cell clones recognized (subsets of) peripheral blood cells as well as CML cells, except for the T-cell clone for TRIP10. Recognition of (subsets of) peripheral blood cells was also observed for all CD4+ T-cell clones, but CML cells were differentially recognized. CML cells were strongly recognized by the T-cell clones for MTHFD1 and the unknown mHag in HLA-DR, whereas no or low reactivity was observed for all other CD4+ T-cell clones. All CD8+ and CD4+ T-cell clones strongly recognized professional APC, including monocyte-derived dendritic cells and in vitro differentiated CML cells with APC phenotype. All T-cell clones were also capable of recognizing AML and ALL, except for the T-cell clone for TRIP10, which showed restricted recognition of AML-M4 and -M5 of monocytic origin. As non-hematopoietic cells, patient-derived fibroblasts were cultured with and without IFN-γ and tested for T-cell recognition. In the absence of IFN-γ, all T-cell clones failed to recognize fibroblasts, except for the T-cell clone for the unknown mHag in B*0801. After treatment with IFN-γ, additional reactivity was observed for the T-cell clones for SON DNA-binding protein and the unknown mHag in B*4001. Our data showed the specificity and diversity of mHags recognized by T-cells induced in a patient successfully treated with DLI for relapsed CML. The T-cell response was directed against 13 different mHags, of which 10 mHags in HLA class I and class II have now been identified by different techniques. Detailed analysis of T-cell recognition of hematopoietic and non-hematopoietic cells provides evidence that the mHags played different roles in the onset and execution of GvL and GvHD. Moreover, only one of the 10 identified mHags was expressed on fibroblasts after treatment with IFN-γ, indicating the characterization of mHags with potential relevance for T-cell based immunotherapy. Disclosures: No relevant conflicts of interest to declare.

Identification of T Cell Epitope of ADAMTS13 in Thrombotic Thrombocytopenic Purpura Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 106-106 ◽  
Author(s):  
Laurent Gilardin ◽  
Sandrine Delignat ◽  
Bernard Maillere ◽  
Bagirath Gangadharan ◽  
Ivan Peyron ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd4 T Cells ◽  
Binding Capacity ◽  
Cell Epitope ◽  
Interferon Γ ◽  
Cd4 T Cell ◽  
T Cell Epitope ◽  
T Cell Lines

Abstract Introduction: Thrombotic Thrombocytopenic Purpura (TTP) results from the development of auto-antibodies directed against A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13th member (A13). The implication of CD4+ T-cells in the pathogenesis of the disease is suggested by the existence of a restriction to HLA DRB1*11 allele and by the isotype switch of the antibodies. However, T-cell autoimmune response to A13 and the properties of CD4+ T-cells from TTP patients have never been studied. Here, we determined the immunodominant T-cell epitope of A13 in TTP patients. Methods: Using the IEDB website, we predicted in silico the immunodominant peptides of A13 based on their binding capacity to HLA DR11 haplotype. Subsequently, these peptides were synthesized and validated in vitro for their binding capacity to purified HLA-DR11 molecules using an ELISA competitive assay. The peptides that bound with the best capacity to HLA-DRB1*11 molecule were then tested for their recognition by human CD4+ T-cells from HLA DRB1*11 healthy donors and patients, at diagnosis or in remission. To this end, CD4+ T-cells were repetitively stimulated with HLA-DRB1*11 monocyte-derived dendritic cells loaded with the peptides and T-cell line were generated after amplification of interferon-γ secreting cells selected upon stimulation. The effect of individual peptide on activation of the established CD4+ T-cell line was assessed by interferon-γ (IFNγ) ELISPOT. Next, we evaluated the promiscuous HLA-binding capacity of the DRB1*11 identified peptides using the same method in HLA DRB1*01 TTP patients. Finally, in order to validate the involvement of these peptides in an immune response toward A13 in vivo, we immunized a humanized HLA DRB1*01-transgenic H-2 class I-/class II-knockout mouse with full length recombinant human A13 (rhA13). We then generated A13-specific T-cell hybridomas restricted to human HLA DRB1*01 and investigated whether the peptides previously identified were recognized by the hybridomas. Results A first list of 48 peptides with reliable predicted binding scores was elaborated through IEDB analysis. Of these, twenty-one peptides demonstrated a high binding capacity to HLA DRB1*11 molecules on ELISA competitive assay. These were selected to stimulate human CD4+ T-cells and we generated CD4+ T-cell lines from HLA DRB1*11 healthy donors and patients (n=5). Six A13 derived peptides were able to activate CD4+ T-cell lines, as revealed by IFNγ secretion by ELISPOT. The peptides were identified to be located within different domains of the protein but more particularly in the spacer and CUB2 domains. Interestingly, two of the identified peptides demonstrated promiscuity based on their ability to activate a CD4+ T-cell line we generated from a HLA DRB1*01 TTP patient. In parallel studies, using HLA DRB1*01 transgenic mice immunized with rhA13, we generated A13-specific T-cell hybridomas. The screening of their specificity allowed us to identify only one A13 derived peptide. The sequence of the peptide, located within the CUB2 domain, was precisely determined, it is promiscuous between DRB1*01 and DRB1*11 haplotype and represents the immunodominant CD4+ T-cell epitope of ADAMTS13. Conclusion: We identified several undescribed CD4+T-cell epitopes of A13 in HLA DRB1*1101 patients. They are located in different domains of the protein, particularly in the spacer and CUB2 domains. One of them, located in the CUB2 domain, is promiscuous to HLA DRB1*0101 and responsible for the immunodominant response to A13. The results we obtained, lead us to generate the tools to study the specific cells involved in the origin of the physiopathological process of the disease. Disclosures Coppo: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

scholarly journals T cell recognition of major histocompatibility complex class II complexes with invariant chain processing intermediates.

1995 ◽  
Vol 182 (5) ◽  
pp. 1403-1413 ◽  
Author(s):  
S Morkowski ◽  
A W Goldrath ◽  
S Eastman ◽  
L Ramachandra ◽  
D C Freed ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Invariant Chain ◽  
Cell Recognition ◽  
T Cell Recognition ◽  
Histocompatibility Complex ◽  
Mutant Cells

Peptides from the lumenal portion of invariant chain (Ii) spanning residues 80-106 (class II-associated Ii peptide [CLIP]) are found in association with several mouse and human major histocompatibility complex (MHC) class II allelic variants in wild-type and presentation-deficient mutant cells. The ready detection of these complexes suggests that such an intermediate is essential to the MHC class II processing pathway. In this study, we demonstrate that T cells recognize CLIP/MHC class II complexes on the surface of normal and mutant cells in a manner indistinguishable from that of nominal antigenic peptides. Surprisingly, T cell hybrids specific for human CLIP bound to murine MHC class II molecule I-Ab and a new monoclonal antibody 30-2 with the same specificity, recognize two independent epitopes expressed on this peptide/class II complex. T cell recognition is dependent on a Gln residue (position 100) in CLIP, whereas the 30-2 antibody recognizes a Lys residue-at position 90. These two residues flank the 91-99 sequence that is conserved among human, mouse, and rat Ii, potentially representing an MHC class II-binding site. Our results suggest that the COOH-terminal portion of CLIP that includes TCR contact residue Gln 100 binds in the groove of I-Ab molecule. Moreover, both T cells and the antibody recognize I-Ab complexed with larger Ii processing intermediates such as the approximately 12-kD small leupeptin-induced protein (SLIP) fragments. Thus, SLIP fragments contain a CLIP region bound to MHC class II molecule in a conformation identical to that of a free CLIP peptide. Finally, our data suggest that SLIP/MHC class II complexes are precursors of CLIP/MHC class II complexes.

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